J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 807–810
809
imidazole ring MOM-protecting group. Because of this problem,
complete cleavage directly to the amino acid was carried out with
aqueous HCl. The resulting mixture of (S)-4-fluorohisitidine and
valine was converted to the N-trifluoroacetyl methyl ester
derivatives by sequential treatment with methanolic HCl and
trifluoroacetic anhydride. N-Trifluoroacetyl-(S)-4-fluorohisitidine
methyl ester 10 was separated by flash chromatography and
purified. This was then saponified and isolated as the free amino
After drying (Na2SO4) and removal of the solvent, flash chromato-
graphy (hexane/EtOAc, 75:25 ! 25:75) produced 2.74 g (54%
yield) of 6. This was identical in all respects with material
prepared previously [1,2].
3.4. 5-Fluoro-1-methoxymethyl-1H-imidazole-4-carboxylic acid
ethyl ester (7)
acid
2
by Dowex chromatography and lyophillization. This
A solution of 6 (1.70 g, 11.8 mmol) in 100 mL of CH2Cl2 was
chilled to ꢀ12 8C and 2.5 mL (15 mmol) of DIPEA was added. After
15 min, MOMCl (1.2 mL, 15.7 mmol) was added dropwise. The
reaction was kept at ꢀ12 8C for 1 h and then was allowed to warm
to room temperature for 30 min. The reaction was poured into
water (200 mL) and extracted with CH2Cl2 (3ꢂ 100 mL). After
washing with brine and drying (Na2SO4), removal of the solvent
produced 2.43 g (>100% yield) of 7 as a clear light yellow oil. This
was of sufficient purity to use in the next step, but a short plug of
silica could be used to remove the minor impurities to give 2.36 g
(98% yield) of 7. In general, yields of ꢁ98% were obtained in this
reaction. 1H (CDCl3): 1.38 (t, 3H, CH3, 3JHH = 7.2), 3.37 (s, 3H, CH3),
material was identical to that made by previous procedures [2,9].
The spectral and data physical, including rotation, of 2 prepared
by this route were in complete agreement with authentic
compound characterized from previous syntheses. The use of
microwave irradiation in preparation of starting material and
improvement of the key reduction step are important advances
from this synthesis.
3. Experimental
3.1. General
3
4
4.36 (q, 2H, JHH = 7.2), 5.59 (d, 2H, CH2, JHF = 0.9), 7.43 (d, 1H,
4
All the reagents were from commercial sources and used
without further purification. NMR spectra were run in CDCl3 on a
Varian Gemini 300 MHz spectrometer. Mass spectra were deter-
mined using a Jeol SX-102 instrument.
imid. C2–H, JHF = 1.5). 13C (CDCl3): 14.26 (s, CH3), 56.73 (s, CH3),
2
60.88 (s, CH2), 78.15 (s, CH2), 102.88 (d, imid. C4, JCF = 28.7),
135.42 (d, imid. CH, 3JCF = 15.4), 159.17 (d, CO, 3JCF = 5.1), 159.66 (d,
imid. CF, 1JCF = 253.3). 19F (CDCl3): ꢀ113.88 (s, 1F). HR-MS (ESI): for
C8H12N2O3F calculated 203.0832 (M+1), found 203.0832 (M+1).
Anal. Calcd. for C8H11N2O3F: C, 47.52; H, 5.48. Found: C, 47.46; H,
5.50.
3.2. Ethyl 4-aminoimidazole-5-carboxylate (5)
To a solution of 25 g (0.154 mol) of 4-aminoimidazole-5-
carboxamide hydrochloride in 180 mL of ethanol was added 60 mL
3.5. (5-Fluoro-1-methoxymethyl-1H-imidazol-4-yl)-methanol (8)
of methane sulfonic acid. After initial mixing,
a lavender
precipitate formed and the microwave container was sealed.
The mixture was subjected to microwave radiation (variable
voltage) to 155–165 8C (the temperature was adjusted to keep
vessel pressure under 21 bar). Upon cooling, the precipitate that
formed in the reaction vessel was removed by vacuum filtration
and was washed with several aliquots of ethanol. The precipitate
was dissolved in water and the pH was checked and adjusted to
neutrality. The filtrate was neutralized with 6 M NaOH and the
solvent was removed by rotary evaporation. This material was
combined with the solution of salts originally precipitated from the
aqueous solution above and extracted multiple times (ꢁ5
extraction) with allotments of EtOAc (ꢁ200 mL). The combined
EtOAc extracts were washed (H2O, brine) and then dried over
sodium sulfate. Removal of the solvent produced 5 as a white solid.
This was purified either by fractional crystallization (EtOAc/
ethanol) or column chromatography (DCM/MeOH w/0.1% Et3N). 4-
Aminoimidazole-5-carboxylate ethyl ester (5) was obtained as
colorless crystals in yields ranging from 7 to 9 g (29–37%) in
multiple runs. This was identical in all respects to material
obtained previously using thermal ethanolysis [2].
A solution of 7 (2.14 g, 10.6 mmol) in ether (35 mL) under a N2
atmosphere was cooled to ꢀ78 8C. To this was added dropwise a
solution of 44 mL (22 mmol) of 0.5 M LAH in diglyme. The reaction
was allowed to gradually warm to room temperature over night.
Cold water saturated with CO2 then was added dropwise to quench
the reaction. The aluminum oxide salts were removed by filtration
and were subjected to soxhlet extraction with EtOAc for 3 h to
separate the additional 8 from the salts. The original filtrate was
extracted with EtOAc and combined with the solution from the
soxhlet extraction. After drying, removal of EtOAc followed by
column chromatography (hexane/EtOAc, 1:1) produced 1.60 g
(10 mmol, 95% yield) of 8. 1H (CDCl3): 3.31 (d, 3H, CH3, 4JHF = 2.4),
3.64 (s, 1H, OH), 4.62 (bs, 2H, CH2), 5.29 (d, 2H, CH2, 4JHF = 1.2), 7.19
(d, 1H, imid. C2–H, 4JHF = 1.5). 13C (CDCl3): 51.16 (d, CH2, 3JCF = 3.7),
2
56.25 (s, CH3), 77.44 (s, CH2), 109.38 (d, imid. C4, JCF = 33.5),
3
1
131.26 (d, imid. CH, JCF = 16.0), 154.62 (d, imid. CF, JCF = 238.4).
19F (CDCl3): ꢀ137.13 (s, 1F). HR-MS (ESI): for C6H10N2O2F
calculated 161.0726 (M+1), found 161.0733 (M+1). Anal. Calcd.
for C6H9N2O2F: C, 45.00; H, 5.66. Found: C, 44.65; H, 5.75.
3.6. 2-(5-Fluoro-1-methoxymethyl-1H-imidazol-4-ylmethyl)-5-
3.3. Ethyl 4-fluoroimidazole-5-carboxylate (6)
isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (9)
A solution of 4.98 g (32.1 mmol) of 5 in 100 mL of 48% HBF4 was
cooled to ꢀ12 8C and a solution 2.88 g (41.7 mmol) of NaNO2
dissolved in a minimal amount of water was added dropwise with
stirring. After 15 min, the reaction mixture was transferred to a
200 mL photochemical reaction flask and filled with cold HBF4. The
solution then was cooled to ꢀ78 8C with dry ice/acetone and
irradiated for 90–120 min using a Hanovia medium pressure
ultraviolet lamp and quartz immersion well fitted with a corex
filter. The resulting solution was neutralized (50% NaOH) at ꢀ78 8C,
and after warming to room temperature was extracted with
aliquots of EtOAc (4–6 times with 200–300 mL per extraction).
To a solution of 8 (1.66 g, 10.4 mmol) and CaH2 (895 mg,
21.3 mmol) in 15 mL of THF cooled to ꢀ78 8C under N2 was added a
solution of PBr3 (1.05 g, 3.89 mmol) in 10 mL of THF. The reaction
was allowed to gradually warm to room temperature overnight.
TLC confirmed completion of the reaction at this time and the
solution was cooled to ꢀ100 8C. A solution of lithiated 3 was
prepared in the usual manner. Thus, 6.96 mL (17 mmol) of a 2.5 M
solution of nBuLi in hexanes was added dropwise to a solution of
the pyrazine 3 (3.24 g, 17.6 mmol) in 15 mL of THF cooled to
ꢀ78 8C. After stirring at ꢀ78 8C for 30 min, the solution of 3 was
cooled to ꢀ100 8C. The resulting lithiated pyrazine 3 was then